Wilson disease, ABCC2 c.3972C \> T polymorphism and primary liver cancers: suggestions from a familial cluster

Our plain-English summary of Wilson disease, ABCC2 c.3972C > T polymorphism and primary liver cancers: suggestions from a familial cluster, by G. Brandi, A. Rizzo, M. Deserti, et al (BMC Medical Genetics, 2020).

The study

• Authors: G. Brandi, A. Rizzo, M. Deserti, V. Relli, V. Indio, S. Bin, M. Pariali, A. Palloni, S. De Lorenzo, F. Tovoli, S. Tavolari
• Journal: BMC Medical Genetics
• Published: 2020;21(1):225
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Polymorphisms in genes modulating xenobiotics metabolism, in particular the ABCC2 c.3972C > T single nucleotide polymorphism (SNP) at exon 28, have been suggested to increase primary liver cancer (PLC) risk. Conversely, the occurrence of PLCs in Wilson disease patients is a rare event, in contrast with the occurrence observed in other chronic liver diseases. Here we report the clinical case of five siblings carrying the ABCC2 c.3972C > T SNP; three of them were affected by Wilson disease and two brothers with Wilson disease also developed PLCs.

Methods: The presence of the ABCC2 c.3972C > T SNP was assessed by Sanger sequencing and the exposure of PLC risk factors by standardized questionnaires.

Results: Notably, PLCs occurred only in the two brothers with the ABCC2 c.3972C > T SNP and Wilson disease who resulted exposed to asbestos and cigarette smoking, but not in the other siblings with the ABCC2 c.3972C > T SNP, alone or in association with Wilson disease, not exposed to these carcinogens and/or to other known risk factors for PLCs.

Conclusions: These findings suggest that ABCC2 c.3972C > T SNP and WD, also in association, may not represent a sufficient condition for PLC development, but that co-occurrence of further host/exogenous risk factors are needed to drive this process, reinforcing the notion that liver carcinogenesis is the result of a complex interplay between environmental and host genetic determinants. Due to the sporadic cases of this study and the paucity of data currently available in literature on this issue, future investigations in a larger population are needed to confirm our findings.

In plain English

This article reported one family: five siblings studied by the authors, who work in Bologna, Italy. The authors sequenced DNA from blood samples to look for a genetic variant, ABCC2 c.3972C > T, which earlier studies had linked to primary liver cancer. They also used standardized questionnaires to ask about smoking and asbestos exposure. All five siblings carried the variant, and three also had Wilson disease. Two brothers with Wilson disease developed primary liver cancers. One had intrahepatic cholangiocarcinoma and later hepatocellular carcinoma. The other had intrahepatic cholangiocarcinoma removed by surgery. New liver lesions later found were suspected to be a recurrence, and he was treated with chemotherapy and a liver transplant. Both brothers had worked as railroaders, were heavy smokers (more than 45 and more than 50 pack-years), and were classed as moderately exposed to asbestos. No fiber type was given. The other three siblings, including a sister with Wilson disease, had no liver cancer and no such exposures. The authors concluded that the variant and Wilson disease may not be enough by themselves for liver cancer to develop. They said larger studies are needed because so few cases were studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Report of a family cluster (case series of five siblings) with genetic testing and risk-factor questionnaires
• Who was studied: Five siblings from one family; three had Wilson disease, and two brothers with Wilson disease developed primary liver cancers (cancers diagnosed 2013 to 2016)
• Exposure: Asbestos exposure assessed with the Italian National Registry of Mesotheliomas (ReNaM) questionnaire, plus cigarette smoking. The two brothers with liver cancer both worked as railroaders and were classed as moderately exposed to asbestos and as heavy active smokers. No fiber type or measured dose was reported.
• Main results:
  • All five siblings carried the ABCC2 c.3972C > T variant
  • First brother (age 56 at presentation in December 2013, Wilson disease diagnosed at 43): more than 45 pack-years of smoking and a job as a railroader. He had intrahepatic cholangiocarcinoma removed, then hepatocellular carcinoma in May 2014. He was without evidence of disease for over 5 years.
  • First brother: a second liver tumour removed in May 2014 was hepatocellular carcinoma, and he stayed free of disease afterwards
  • Second brother (Wilson disease diagnosed at 36): intrahepatic cholangiocarcinoma was found in December 2016 and removed by surgery in January 2017. In January 2018, at least six liver lesions were found that were suspected to be a recurrence.
  • Second brother: after the suspected recurrence, he was treated with Gemcitabine-Cisplatin and then a liver transplant. He was without evidence of disease 1 year after the transplant. He had more than 50 pack-years of smoking and worked as a railroader.
  • Of the other three siblings, a sister had Wilson disease (diagnosed at 31). The other two had no Wilson disease, and none of the three had liver cancer.
  • No known liver cancer risk factors, including smoking and asbestos, were found in the other three siblings
• The authors' conclusion: The authors concluded that the ABCC2 c.3972C > T variant and Wilson disease, alone or together, may not be sufficient for primary liver cancer to develop. In their view, further host or outside risk factors, such as the smoking and asbestos exposure seen in the two brothers, are likely needed.
• Limitations the authors state:
  • The mother and other relatives could not be tested, so the authors could not trace how Wilson disease and the variant were inherited in the family
  • Only a few sporadic cases were studied, and little published data exist, so larger studies are needed to confirm the findings

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis.

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